rs1994798

Variant names:

• chr1-11794698-G-A
• rs1994798
• NM_005957.5:c.1166+31C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.1166+31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,613,318 control chromosomes in the GnomAD database, including 280,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24790 hom., cov: 32)
  • Exomes 𝑓: 0.59 (256165 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.42
• Publications: 36 publications found

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-11794698-G-A is Benign according to our data. Variant chr1-11794698-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1166+31C>T		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.1289+31C>T		intron	N/A	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1286+31C>T		intron	N/A	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1166+31C>T		intron	N/A	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1286+31C>T		intron	N/A	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1166+31C>T		intron	N/A	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85364 AN: 151888 Hom.: 24771 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.563

GnomAD2 exomes AF: 0.607 AC: 152736 AN: 251438 AF XY: 0.599

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.602

GnomAD4 exome AF: 0.588 AC: 859672 AN: 1461312 Hom.: 256165 Cov.: 49 AF XY: 0.584 AC XY: 424900 AN XY: 727012

African (AFR) AF: 0.435 AC: 14569 AN: 33468

American (AMR) AF: 0.761 AC: 34017 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 16044 AN: 26130

East Asian (EAS) AF: 0.774 AC: 30735 AN: 39700

South Asian (SAS) AF: 0.469 AC: 40469 AN: 86242

European-Finnish (FIN) AF: 0.650 AC: 34687 AN: 53390

Middle Eastern (MID) AF: 0.473 AC: 2730 AN: 5768

European-Non Finnish (NFE) AF: 0.586 AC: 651355 AN: 1111520

Other (OTH) AF: 0.581 AC: 35066 AN: 60372

GnomAD4 genome AF: 0.562 AC: 85425 AN: 152006 Hom.: 24790 Cov.: 32 AF XY: 0.565 AC XY: 41967 AN XY: 74274

African (AFR) AF: 0.436 AC: 18084 AN: 41452

American (AMR) AF: 0.688 AC: 10519 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2142 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3908 AN: 5146

South Asian (SAS) AF: 0.483 AC: 2325 AN: 4810

European-Finnish (FIN) AF: 0.640 AC: 6760 AN: 10556

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39801 AN: 67972

Other (OTH) AF: 0.562 AC: 1187 AN: 2112

Alfa AF: 0.588 Hom.: 8580

Bravo AF: 0.564

Asia WGS AF: 0.617 AC: 2147 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.023
DANN	Benign	0.69
PhyloP100		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1994798; hg19: chr1-11854755; COSMIC: COSV64877997; COSMIC: COSV64877997;